This is a new R21 application to study the role of a neuronal calcium channel in determining susceptibility to bipolar disorder. All excitable cells use calcium ion channels on their surface to read electrical signals and convert them into a change in intracellular calcium, a ubiquitous second messenger. Calcium controls a huge number of cellular processes including muscle contraction, neurotransmitter release, cell death and neuronal growth. Calcium ion channels are important drug targets for treating hypertension and neuropathic pain. Mutations in the CACNA1C calcium ion channel gene cause a rare hereditary disorder Timothy Syndrome and single nucleotide polymorphisms identified very recently in the same CACNA1C gene associate with bipolar disorder. Bipolar disorder is a chronic mental illness affecting close to 6 million adults in the United States characterized by cyclical episodes of mania and depression. The most common treatment is lithium but this agent is only partially effective, has numerous side effects, and a low safety margin. There is a clear inheritable risk in bipolar disorder. Recently a large, collaborative genome-wide association study analyzed >10,000 bipolar and control individuals and identified a region in human chromosome 12 that has significant association with bipolar disorder. Bipolar disease-associated single nucleotide polymorphisms mapped to a long intron in an uncharacterized region of the CACNA1C gene. This exciting discovery affords us a unique opportunity to understand how single nucleotide variations in the CACNA1C gene could disrupt normal calcium channel activity in the brain. We will use a combination of gene and RNA analyses, and electrophysiological recordings to explore how this potential site of bipolar susceptibility in CACNA1C controls calcium ion channel function. Our work has the potential to provide novel insights into the molecular mechanisms underlying bipolar disorder. ) PUBLIC HEALTH RELEVANCE: This R21 project will test the hypothesis that a long intron in the CACNA1C gene, recently identified as a risk factor in bipolar disorder, controls calcium channel function through alternative pre-mRNA splicing. We will use a combination of RNA, gene, and electrophysiological analyses to reveal the functional role of intron 4 in controlling L-type calcium channel activity in neurons.